Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Germline gain-of-function (GOF) mutations in PIK3CD cause a novel inborn error of immunity.
• These mutations lead to hyperactivation of the PI3K-AKT-mTOR pathway.
• Clinical manifestations include recurrent infections, autoimmunity, and increased risk of B-cell lymphoproliferation and lymphoma.

Purpose of the Study:

• To understand the mechanisms of inefficient surveillance of EBV-infected B cells in PIK3CD GOF patients.
• To identify key molecules involved in cell-mediated immunity against EBV.
• To inform the development of immunotherapeutic interventions for PIK3CD GOF and other EBV-related disorders.

Main Methods:

• Investigated the impact of PIK3CD GOF mutations on CD8+ T cell and natural killer (NK) cell generation, differentiation, and function.
• Utilized a novel mouse model recapitulating PI3K GOF mutations.
• Analyzed T cell and NK cell responses against Epstein-Barr virus (EBV).

Main Results:

• CD8+ T cells exhibited an effector phenotype with markers of premature immunosenescence/exhaustion and increased susceptibility to cell death.
• NK cells showed altered expression of differentiation markers.
• Both CD8+ T and NK cells demonstrated a reduced ability to eliminate EBV-infected B cells.
• PIK3CD GOF B cells displayed increased expression of CD48, PD-L1/2, and CD70.

Conclusions:

• PIK3CD GOF mutations induce aberrant T cell and NK cell exhaustion and senescence.
• Impaired cytotoxicity of CD8+ T and NK cells may contribute to clinical features like herpesvirus susceptibility and reduced tumor surveillance.
• These findings elucidate critical immune defects in PIK3CD GOF and suggest therapeutic targets.